Progesterone receptor (PR) mediates the actions of the ovarian steroid progesterone, which together with estradiol regulates gonadotropin secretion, prepares the endometrium for implantation, maintains pregnancy, and differentiates breast tissue. Separation of estrogen and progesterone actions in hormone-responsive tissues remains a challenge. Pathologies of the uterus and breast, including endometrial cancer, endometriosis, uterine fibroids, and breast cancer, are highly associated with estrogen, considered to be the mitogenic factor. Emerging evidence supports distinct roles of progesterone and its influence on the pathogenesis of these diseases. Progesterone antagonizes estrogen-driven growth in the endometrium, and insufficient progesterone action strikingly increases the risk of endometrial cancer. In endometriosis, eutopic and ectopic tissues do not respond sufficiently to progesterone and are considered to be progesterone-resistant, which contributes to proliferation and survival. In uterine fibroids, progesterone promotes growth by increasing proliferation, cellular hypertrophy, and deposition of extracellular matrix. In normal mammary tissue and breast cancer, progesterone is pro-proliferative and carcinogenic. A key difference between these tissues that could explain the diverse effects of progesterone is the paracrine interactions of PR-expressing stroma and epithelium. Normal endometrium is a mucosa containing large quantities of distinct stromal cells with abundant PR, which influences epithelial cell proliferation and differentiation and protects against carcinogenic transformation. In contrast, the primary target cells of progesterone in the breast and fibroids are the mammary epithelial cells and the leiomyoma cells, which lack specifically organized stromal components with significant PR expression. This review provides a unifying perspective for the diverse effects of progesterone across human tissues and diseases.

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Progesterone Action in Endometrial Cancer, Endometriosis, Uterine Fibroids, and Breast Cancer

The biology of progesterone receptor in the normal mammary gland and in breast cancer.

The steroid hormone, progesterone (P), is a central coordinator of all aspects of female reproductive activity and plays a key role in pregnancy-associated mammary gland morphogenesis and mammary tumorigenesis. The effects of P on the mammary gland are mediated by two structurally and functionally distinct nuclear receptors PR-A and PR-B that arise from a single gene. Null mutation of both receptors in PR knockout (PRKO) mice has demonstrated a critical role for PRs in mediating pregnancy-associated mammary ductal branching and lobuloalveolar differentiation and in initiation of mammary tumors in response to carcinogen. Analysis of the molecular genetic pathways disrupted in PRKO mice has recently yielded important insights into the molecular mechanisms of regulation of mammary gland morphogenesis by PRs. In addition to its essential role in regulating proliferative and differentiative responses of the adult mammary gland during pregnancy, P plays a critical role in the protection against mammary tumorigenesis afforded by early parity. Thus, the effects of P on postnatal developmental plasticity of the mammary gland differ between young and adult glands. This review will summarize recent advances in our understanding of 1) the molecular mechanisms by which PRs mediate pregnancy-associated mammary gland morphogenesis, 2) the role of PRs in mediating tumorigenic responses of the adult mammary gland to carcinogen, and 3) the role of P in long-term protection of the juvenile mammary gland against tumorigenesis. In addition, we will summarize recent insights into the isoform selective contributions to some of these activities of PRs obtained from comparative analysis of P-dependent mammary gland development in PR isoform specific knockout mice lacking either the PR-A (PRAKO) or PR-B (PRBKO).

Progesterone receptors in mammary gland development and tumorigenesis.

Progesterone Receptor Signaling Mechanisms.

In this report, we evaluate the effects of a 21-substituted-19-nor-progestin, CDB-4124, on 7,12,-dimethylbenz(a)anthracene (DMBA)-induced mammary carcinogenesis in rats in comparison with RU486. Sprague-Dawley female rats were treated with DMBA at 50 days of age in order to induce mammary tumors. When the tumors reached the size of 10-12 mm, the animals were treated for 28 days with the vehicle, RU486, progesterone, CDB-4124 at various doses, or CDB-4124 plus progesterone. Anti-progestins resulted in the regression in the size of the existing tumors, and in the suppressed development of new tumors and tumor multiplicity. Progesterone treatment, however, increased the size and multiplicity. Progesterone rendered an increased number of growing tumors as compared to the regression in the anti-progesterone treatment groups. The combination of CDB-4124 and high doses of progesterone opposed the efficacy of CDB-4124. The growth inhibitory effects of the anti-progestins were correlated with increased apoptosis and reduced cell proliferation. These results indicate that anti-progestins should be developed for the chemoprevention and treatment of hormone-responsive breast cancer.

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Anti-progestins suppress the growth of established tumors induced by 7,12-dimethylbenz(a)anthracene: Comparison between RU486 and a new 21-substituted-19-nor-progestin

Role of the progesterone receptor (PR) in susceptibility of mouse mammary gland to 7,12-dimethylbenz[a]anthracene-induced hormone-independent preneoplastic lesions in vitro.

Ashley Pletz

Papers

Role of the progesterone receptor (PR) in susceptibility of mouse mammary gland to 7,12-dimethylbenz[a]anthracene-induced hormone-independent preneoplastic lesions in vitro.